This invention relates to solid phase nitrile synthesis and particularly, although not exclusively, provides a method of preparing a nitrile compound.
An object of the present invention is to provide an advantageous method of preparing a nitrile compound.
According to the invention, there is provided a method of preparing a nitrile compound, the method comprising treating a solid supported amide to cause formation of the nitrile compound and cleavage from the support.
Thus, there is suitably provided a solid phase reaction which allows formation of nitrites with concomitant release of the solid support. Preferably, in the method, the amide is dehydrated. Preferably the amide is treated such that cleavage and dehydration of the amide are accomplished in one operation.
Said nitrile compound is preferably of formula RCN where R represents an optionally-substituted alicyclic, aliphatic or aromatic (which includes heteroaromatic) group.
Except where otherwise stated in this specification, an alicyclic group may have five or six carbon atoms; it preferably has six. Such a group may be optionally-substituted by any atoms or groups hereinafter described. Additionally, a said alicyclic group may be optionally substituted by forming a polycyclic, for example bicyclic, ring system with other cyclic or aromatic groups. In one embodiment, an alicyclic group may form a bicyclic ring system with a five or six-member aromatic group, an example of this arrangement being a tetrahydronaphthyl group.
Except where otherwise stated in this specification, optional substituents of alicyclic, aliphatic and aromatic groups include halogen atoms for example fluorine, chlorine or bromine atoms and optionally-substituted phenyl, nitro, cyano, alkoxy, hydroxy, amino, alkylamino, sulphinyl, alkylsulphinyl, sulphonyl, amido, alkylamido, alkoxycarbonyl, haloalkyoxycarbonyl and haloalkyl groups. optional substituents, especially nucleophilic groups, also include protected forms of any of the aforesaid.
Except where otherwise stated in this specification, an aliphatic group suitably has up to 8, preferably up to 6, more preferably up to 4, especially up to 2, carbon atoms and may be of straight chain or, where possible, branched chain structure.
Except where other stated in this specification, an aromatic group may include a monocyclic or polycyclic (fused) aromatic ring system. Any aromatic ring of such a system may include one or more heteroatoms selected from nitrogen, oxygen and sulphur atoms. Preferred monocyclic or polycyclic groups include five or six ring atoms.
Where R represents an alicyclic group, it is preferably an optionally-substituted group which includes six ring atoms. Preferably said alicyclic group is substituted so as to define a polycyclic group, especially a bicyclic group, suitably wherein one ring thereof is aromatic. An especially preferred alicyclic group is an optionally-substituted, preferably unsubstituted, tetrahydronaphthyl group.
Where R represents an aliphatic group, such a group is preferably substituted. It may be substituted, preferably monosubstituted, suitably by an amino, or a derivative of an amino (especially a protected) group or an optionally-substituted aromatic group. Examples of protected amino groups include Fmoc- and Boc-protecting groups. A preferred aliphatic group R is of formula 
wherein X is a substituent, especially a protected amino group and R1 is an optionally substituted alkyl (preferably a C1-8, more preferably C1-4 alkyl, especially a methyl) group.
Examples of aliphatic groups optionally-substituted by an aromatic group include a C1-8, preferably a C1-6, more preferably a C1-4, especially a C1-2, alkyl group substituted by an optionally-substituted, especially an unsubstituted, phenyl group. A preferred such group is a phenylethylyl group.
Where R represents an aromatic group, it preferably represents an optionally-substituted phenyl or optionally-substituted bicyclic (fused) group. A preferred optionally-substituted phenyl group is substituted by any of the substituents described above, the preferred ones of which include an optionally-substituted phenyl group or a nitro, alkoxy (suitably a C1-8, preferably C1-6, more preferably C1-4, especially a C1, alkoxy) group. A preferred bicyclic (fused) group comprises a benzo moiety fused to a five-membered heteroaromatic moiety and preferably represents a benzoheterophenyl (e.g. benzothiophenyl) group.
Preferably, group R incorporates an aromatic moiety and/or an amino group, especially a protected amino group. More preferably, group R incorporates an aromatic moiety.
Said amide may be of formula
RCONR2-SSxe2x80x83xe2x80x83II
wherein R2 is a hydrogen atom or an optionally-substituted alkyl group and SS represents a solid support.
R2 is preferably a hydrogen atom.
SS preferably includes a moiety of formula 
wherein the free bond is bonded to the nitrogen atom in the amide of formula II and wherein R3, R4 and R5, independently represent a hydrogen atom or an optionally-substituted alkyl or aromatic group, provided that at least one of groups R3, R4, or R5 represents an optionally-substituted aromatic group. Atoms or groups on one of R3 R4 or R5 may be bonded to another one of R3 R4 or R5 so that bridging atoms or groups are defined between a part of one of R3, R4 or R5 and a part of another of R3, R4 or R5
Preferably, R5 represents a hydrogen atom or an optionally-substituted, especially an unsubstituted, alkyl group. More preferably, R5 represents a hydrogen atom.
Preferably, R3 does not represent a hydrogen atom. Preferably, R3 represents an electron-donating group. R3 preferably represents an optionally-substituted aromatic group. R3 may be optionally-substituted by one or more electron donating groups, for example by alkoxy, preferably C1-4, more preferably C1-2, especially methoxy, groups. Preferably, R3 represents an optionally-substituted phenyl group. R3 may be optionally-substituted by a bridging atom or group which defines a bridge between groups R3 and R4
Wherein R3 is substituted, it is preferably substituted in the ortho- and/or para-position(s).
Preferably, R4 does not represent a hydrogen atom. Preferably, R4 represents an electron-donating group. R4 preferably represents an optionally-substituted aromatic group. R4 may be substituted by one or more electron-donating groups, for example by a group incorporating an xe2x80x94Oxe2x80x94 moiety. Preferably R4, represents an optionally-substituted phenyl group. Where a bridge is defined between groups R3 and R4 said bridge may be defined by xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 moieties, especially by an xe2x80x94Oxe2x80x94 moiety which suitably forms with part of groups R3 and R4 a component of a six-membered ring. Where R4 is substituted, it is preferably substituted in the ortho and/or para position(s).
Preferably, one of R3 and R4, more preferably R4, is linked to a polymer support.
In one embodiment, SS may represent 
wherein PS represents a polymer-support and the free bond between the phenyl groups represents the point of attachment to the nitrogen atom in formula II.
In another embodiment, SS may represent 
where the free bond is as described above.
Preferably the method comprises treating said solid supported amide to cause formation of the nitrile compound and cleavage of it from the support.
Preferably, in the method, formation of the nitrile compound and cleavage of it from the support occur substantially concurrently.
Preferably, preparation of said nitrile compound involves dehydrating said solid supported amide. In the preparation of the nitrile compound, the amide may be acetylated, suitably by trifluoroacetylation, which suitably allows cleavage/dehydration in one operation. Dehydration may be undertaken in the presence of a base. Preferred dehydrating agents are highly electrophilic and may include: a nitrogen-containing base, for example an aromatic nitrogen containing base such as pyridine; an acid halide, especially an acid chloride and preferably one including an electron withdrawing group attached to the carbonyl carbon thereof, wherein suitably a haloalkyl, preferably a chloroalkyl, especially a multi-chloro alkyl, such as trichloromethyl, may be used; and Burgess reagent ((methoxycarbonylsulphamoyl)triethylammonium hydroxide inner salt).
The treatment of said solid supported amide is preferably carried out in an aprotic suitably an organic solvent. The reaction is suitably carried out at a temperature of less than 100xc2x0 C., preferably less than 50xc2x0 C., more preferably at less than 30xc2x0 C., especially at ambient temperature.
After the treatment, the mixture produced may be filtered to separate the nitrile compound from the solid support and then isolated by standard techniques. Said solid supported amide may be prepared by treatment of an amine with a carboxylic acid or a carboxylic acid derivative. Where the nitrile compound is of formula RCN, said amine may be treated with a compound of formula
RCOYxe2x80x83xe2x80x83VI
wherein Y represents an hydroxy group, a carboxylic acid residue, for example a halogen atom or any electron withdrawing leaving group such as those derived from HOBt, HOAt, N-hydroxysuccinimide, 2- or 4-nitrophenol, pentafluorophenol, cyanomethyl and N, Nxe2x80x2-dialkyl-O-acylureas.
The amine used to prepare the amide may be of general formula 
wherein R3, R4 and R5 are as described above.
Preferably, the amide is prepared from the amine by contacting the amine of formula VII with said compound of formula VI, suitably in the presence of a base and suitably in an aprotic organic solvent. The reaction is preferably carried out at a temperature of less than 100xc2x0 C., preferably less than 50xc2x0 C., more preferably less than 30xc2x0 C., especially at ambient temperature.
The invention extends to any novel nitrile compound described herein.
The invention further extends to any novel intermediate described herein.
Specific embodiments of the invention will now be described, by way of example.
Aromatic and aliphatic nitrites have been prepared through dehydration of secondary amides derived from carboxylic acids or carboxylic acid derivatives and resin bound electron rich aromatic methylamines. Schemes 1 and 2 below summarize the preparation starting from Sieber and Rink resins respectively, wherein R is an optionally-substituted aromatic or aliphatic group. 
Referring to schemes 1 and 2, the Sieber and Rink resins are examples of electron rich methylamines which are reacted with carboxylic acids or acid chlorides to prepare secondary amides which can then be dehydrated, for example using excess trifluoracetic anhydride and pyridine in dry dichloromethane overnight to furnish the nitrile derivative (RCN) directly in solution.
Specific reactions undertaken are now described. Examples 1 to 10 describe the preparation of amides; and examples 11 to 24 describe the preparation of nitrile compounds from corresponding amides. In Examples 11 to 18, 23 and 24 dehydration/cleavage to the nitrites is achieved using TFAA-pyr in DCM; in examples 19 and 20, dehydration/cleavage is effected by the use of Burgess reagent; and in Examples 21 and 22 dehydration/cleavage is effected by use of trichloracetyl chloride.
The following abbreviations are used herein:
TBTUxe2x80x942-(1H-benzotriazolyl)-1,1,3,3-tetramethyluronium tetrafluoroborate
HOBtxe2x80x941-hydroxybenzotriazole
DIEAxe2x80x94N,N-diisopropylethylamine
TFAAxe2x80x94trifluoroacetic anhydride
DCMxe2x80x94dichloromethane
DMFxe2x80x94dimethyl formamide
Fmocxe2x80x94fluorenylmethoxycarbonyl
Bocxe2x80x94butoxycarbonyl
Resins described herein were purchased from Nova Biochem. Sieber and Rink resins were purchased in Fmoc protected forms. Deprotection, where necessary, is generally undertaken as follows: Resin (1 g) was suspended in DMF (20 ml) and piperidine (5 ml) was added. The mixture was stirred at room temperature for 30 minutes, then washed with DMF, MeOH, DCM, MeOH, DCM, MeOH and dried in vacuo.
Burgess reagent described herein may be prepared as described in G. M. Atkins, Jr and E. M. Burgess, J. Amer. Chem. Soc., 1968, 90, 4744.